Recent investigations of the joint effects of genetics and environmental exposures on human health have focused on the role of germline polymorphisms in DNA sequences, including single nucleotide polymorphisms (SNPs) and differences in the number of nucleotide repeats. Although such mutations and their interactions with environmental exposures clearly play a role in human diseases, a growing body of evidence indicates that epigenetic changes, especially changes in patterns of DNA methylation, are important contributors to the pathogenesis of human disease. DNA methylation adds a new dimension to the understanding of gene-environment interactions. DNA methylation is uniquely positioned as both an additional source of genetic modification of the response to environmental influences, and is also a potential biomarker of environmental exposure. Despite the evolving evidence for the importance of DNA methylation in human disease pathogenesis, little is known about the environmental determinants of methylation or how gene polymorphisms influence the patterns of epigenetic changes following exposure. The need for a better understanding of the interactions between environmental exposures, polymorphisms and DNA methylation is clear. In this application, the investigators propose to take the next steps beyond studies of the effects of environmental exposures and genetic variation on human diseases, by integrating information on genomic methylation patterns. The broad objectives of this planning application are to develop a framework that will foster a collaborative interdisciplinary research program to study environmental and genetic determinants of DNA methylation patterns and to understand the influence of these epigenetic changes on human disease occurrence in the context of germline DNA variation. The collaborations to be built during the 3-year planning period bring together experienced investigators to develop and utilize evolving biostatistical, molecular, genetic, and epidemiologic methods. At the end of the planning period, they intend to submit an application to establish a Center for Environmental Epigenomics, to be affiliated with the Environmental Genome Project.